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This phase I/II trial studies the side effects and best dose of lenalidomide and to see how well it works in treating patients with acquired immunodeficiency syndrome (AIDS)-related Kaposi sarcoma (KS). Lenalidomide may stop the growth of tumor cells by blocking blood flow to the tumor.

III. Evaluation of time to response, time to relapse, and time to death amongst subjects receiving lenalidomide.

IV. Determine the effect of lenalidomide on human herpesvirus (HHV)-8. V. Assess lenalidomide effects on HHV-8 copy number in peripheral blood mononuclear cell (PBMC), and plasma and whether changes in viral copy number measured in PBMC or plasma are associated with clinical response of KS tumors.

Patients receive lenalidomide PO once daily on days 1-21. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

Drug: Lenalidomide

Lenalidomide is administered daily on days 1-21 of a 28-day cycle. The maximum duration of treatment is 12 28-day cycles. Sequential cohorts were entered at 10 mg/day, 15 mg/day, 20 mg/day and 25 mg/day using a 3+3 design to determine the MTD

Maximum Tolerated Dose of Lenalidomide Defined as the Dose Level at Which 0/6 or 1/6 Subjects Experience Dose Limiting Toxicity (DLT) With the Next Higher Dose Having at Least 2/3 or 2/6 Subjects Encountering DLT (Phase I) [ Time Frame: 28 days ]

Maximum tolerated dose (MTD) of lenalidomide defined as the dose level at which 0/6 or 1/6 subjects experience dose limiting toxicity (DLT) with the next higher dose having at least 2/3 or 2/6 subjects encountering DLT (Phase I). Toxicities will be graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. Using a 3+3 design, the MTD is defined as the level at which 0/6 or 1/6 patients experiences at dose-limiting toxicity in the first cycle.

Tumor Response Rate [ Time Frame: Up to 30 days after completion of study treatment ]

Percentage of patients who achieve a partial or complete response Complete response was defined as the absence of any detectable residual disease, including tumor-associated edema, that persisted for at least 4 weeks.

Partial response was defined as no new lesions (skin or oral), or new visceral sites of involvement (or the appearance or worsening of tumor-associated edema or effusions), and a 50% or greater decrease in the number of all previously existing lesions that lasted for at least 4 weeks, or complete flattening of at least 50% of all previously raised lesions, or a 50% or greater decrease in the sum of the products of the largest perpendicular diameters of the marker lesions.

Secondary Outcome Measures :

Time to Death [ Time Frame: Up to 30 days after completion of study treatment ]

Percentage of patients who died

Time to Relapse [ Time Frame: Up to 30 days after completion of study treatment ]

Percentage of participants who relapsed

Time to Response [ Time Frame: Up to 30 days after completion of study treatment ]

time from enrollment to first response (complete or partial) as defined below: Complete response is defined as the absence of any detectable residual disease, including tumor-associated edema, persisting for at least 4 weeks.

Partial response is defined as no new lesions (skin or oral), or new visceral sites of involvement (or the appearance or worsening of tumor-associated edema or effusions), and a 50% or greater decrease in the number of all previously existing lesions lasting for at least 4 weeks, or complete flattening of at least 50% of all previously raised lesions, or a 50% or greater decrease in the sum of the products of the largest perpendicular diameters of the marker lesions.

Other Outcome Measures:

Relationship Between Clinical Response and Quantitative Measures of Kaposi's Sarcoma-associated Herpesvirus (KSHV)/HHV-8 and HIV Viral Load [ Time Frame: Up to 30 days after completion of study treatment ]

Spearman rank correlation analysis will be used to evaluate the relationship between the qualification of baseline KSHV/HHV-8, HIV viral load and time to progression, and response duration.

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Ages Eligible for Study:

18 Years and older (Adult, Senior)

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

No

Criteria

Inclusion Criteria:

Biopsy-proven KS involving skin with or without visceral involvement either newly diagnosed or refractory to or intolerant of one or more prior therapies

Patients must have cutaneous lesion(s) amenable to four 3 mm tumor biopsies during the study (either 4 separate lesions measuring > 4 mm each OR 2 separate lesions measuring > 8 mm each) and at least five additional lesions measurable for assessment with no improvement over the past month

Serologic documentation of HIV infection by any of the Food and Drug Administration (FDA)-approved tests

Karnofsky performance status >= 60%

Hemoglobin >= 8 g/dL

Absolute neutrophil count (ANC) >= 1,000 cells/mm^3

Platelet count >= 100,000/mm^3

Calculated (method of Cockcroft-Gault) creatinine clearance (CrCl) >= 60 mL/min in the Phase I and CrCl >= 30 mL/min in the Phase II (creatinine clearance may also be obtained by the 24-hour collection method at the investigator's discretion)

Total bilirubin should be =< 1.5x upper limit of normal (ULN); if, however, the elevated bilirubin is felt to be secondary to Atazanavir therapy, patients will be allowed to enroll on protocol if the total bilirubin is =< 3.5 mg/dL provided that the direct bilirubin is normal

Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 10 - 14 days prior to and again within 24 hours prior to starting Cycle 1 of lenalidomide; further, they must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control: one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before starting lenalidomide, during receipt of lenalidomide, and 28 days after discontinuation of lenalidomide; FCBP must also agree to ongoing pregnancy testing; men must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy; all patients must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure

Patients must, in the opinion of the investigator, be capable of complying with the protocol

All patients must be on antiretroviral therapy for HIV infection with CD4 count > 50/mm^3 and viral load < 2,000 copies/mL; patients must be on a stable regimen for at least 12 weeks prior to study entry; patients may receive any FDA approved antiretroviral therapy except for zidovudine

There should be no evidence for improvement in KS in the 3 months prior to study entry, unless there is evidence for progression of KS in the 4 weeks immediately prior to study entry

If antiretroviral regimen contains zidovudine and viral load is suppressed (as measured by HIV viral load =< 200/mL), then antiretroviral therapy must be adjusted to a less toxic therapy not containing zidovudine and enrollment may proceed without waiting 12 weeks; if on zidovudine-containing therapy and viral load is not suppressed (as measured by HIV viral load >= 200/mL), then antiretroviral therapy must be adjusted to a less toxic regimen allowing for optimal viral suppression and must demonstrate stability for at least 12 weeks prior to study entry

Patients with any history of pulmonary embolism (PE) or deep venous thrombosis (DVT) or predisposing clotting risk factors must be on anticoagulation at therapeutic dosing

Exclusion Criteria:

Concurrent, acute, active opportunistic infection other than oral thrush or genital herpes within 14 days of enrollment

Any steroid treatment except for that required for replacement therapy in adrenal insufficiency or inhaled steroids for the treatment of asthma

Patient is =< 2 years free of another primary malignancy; exceptions include the following:

Basal cell skin cancer

Cervical carcinoma in situ

Anal carcinoma in situ

Previous local therapy of any KS-indicator lesion unless the lesion has clearly progressed since treatment; any prior local treatment to indicator lesions regardless of the elapsed time should not be allowed unless there is evidence of clear-cut progression of said lesion

Use of any investigational drug or treatment within 4 weeks prior to enrollment

Physical or psychiatric conditions that in the estimation of the investigator place the patient at high risk of toxicity or non-compliance

Female patients who are pregnant or breast-feeding

Patients with a history of DVT or PE within 1 year

Patients requiring blood transfusions to maintain Hgb eligibility

Patients on erythropoietin-stimulating agents (ESA) unless also on therapeutic anticoagulation

Patients with CD4 < 50 mm^3 and/or viral load > 2,000 copies/mL

Patients on estrogen therapy unless also on therapeutic anticoagulation